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B Lippert

Publications and source records attributed to B Lippert.

At least 19 recordsLinked to original sources
PubMed2002

Pd(II)- and Pt(II)-cimetidine complexes. Crystal structure of trans-[Pt(N,S-cimetidine)(2)]Cl(2)(*)12H(2)O.

The influence of cimetidine on patients under cisplatin treatment for cancer is controversial. It has moderate or no effects on several types of cancer and its effects on the nephrotoxicity induced by cisplatin are uncertain. To examine the binding properties and antiproliferative effects of the known anticancer noble metals, cimetidine (cim) was complexed to platinum(II) and palladium(II). The crystal structure of the Pt-cim compound shows two molecules of cimetidine coordinated to the metal through thioether sulfur and imidazolic nitrogen whereas spectroscopic studies in solution for Pd-cim reveal that the ratio of the metal to cimetidine is 1:1 with identical coordination environments. To determine the antitumor activity of the drugs, the interaction of the metallic complexes and free cimetidine with DNA was assessed. Their cytotoxic activity was compared with that of cisplatin.

Animals↗
PubMed2001

Protonation of platinated adenine nucleobases. Gas phase vs condensed phase picture.

Protonation of adenine carrying a Pt(II) moiety either at N7, N3, or N1 is possible in solution, but the site of protonation is influenced by the location of the Pt(II) electrophile and to some extent also by the overall charge of the metal entity (+2, +1, 0, -1), hence the other ligands (NH(3), Cl(-), OH(-)) bound to Pt(II). Quantum chemical calculations based on density functional theory (DFT) have been carried out for intrinsic protonation energies of adenine complexes carrying the following Pt(II) species at either of the three ring N atoms: [Pt(NH(3))(3)](2+) (1), trans- [Pt(NH(3))(2)Cl](+) (2a), cis-[Pt(NH(3))(2)Cl](+) (2b), trans-[Pt(NH(3))(2)Cl(2)] (3a), cis-[Pt(NH(3))Cl(2)] (3b), [PtCl(3)](-) (4), trans-[Pt(NH(3))(2)OH](+) (5a), cis-[Pt(NH(3))(2)(OH)](+) (5b), trans-[Pt(NH(3))(OH)(2)] (6a), cis-[Pt(NH(3))(OH)(2)] (6b), and [Pt(OH)(3)](-) (7). The data have been compared with results derived from solution studies (water) and X-ray crystallography, whenever available. The electrostatic effects associated with the charge of the metal entity have the major influence on the calculated intrinsic (gas phase) proton affinities, unlike the condensed phase data. Nevertheless, the relative gas phase trends correlate surprisingly well with condensed phase data; i.e., variation of the pK(a) values measured in solution is consistent with the calculated gas phase protonation energies. In addition to a systematic study of the ring proton affinities, proton transfer processes within the platinated adenine species were often observed when investigating Pt adducts with OH(-) ligands, and they are discussed in more detail. To the best of our knowledge, this is the first study attempting to find a systematic correlation between gas phase and condensed phase data on protonation of metalated nucleobases. The gas phase data provide a very useful complement to the condensed phase and X-ray experiments, showing that the gas phase studies are capable of valuable predictions and contribute to our understanding of the solvent and counterion effects on metal-assisted proton shift processes.

Adenine Nucleotides↗
PubMed2001

Metal-modified nucleobase pairs and triplets as cytosine receptors.

A preorganized cationic receptor 2 for cytosine (C) is described which is composed of trans-a2PtII (a= NH3 or CH3NH2) cross-linked modules with adenine (A), guanine (G), and uracil (U) or thymine (T) model nucleobases. The functions of these three modules are as follows: i) Adenine orientates the two other bases at right angles, thus producing the L-shape of the receptor. ii) Guanine is the primary receptor. iii) Uracil or thymine act as coreceptors. Compared with the normal Watson-Crick pair between G and C, the association constant between 2 and C increases by a factor of 3 (in DMSO). As deduced from 1H NMR spectroscopy and confirmed by the X-ray crystal structure of the C adduct 4b, cytosine is fixed through five hydrogen bonds to the receptor, one of which involves the aromatic H(5) of C. A comparison of C binding is made with a structurally related linkage isomer receptor as well as the precursor molecule trans[alpha2PtAG]2+. The potential of modular, cationic receptors is illustrated.

Base Pairing↗
PubMed2001

Formation of ternary complexes by coordination of (diethylenetriamine)-platinum(II) to N1 or N7 of the adenine moiety of the antiviral nucleotide analogue 9.

The synthesis of (Dien)Pt(PMEA-N1), where Dien = diethylenetriamine and PMEA2- = dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is described. The acidity constants of the threefold protonated H3[(Dien)Pt(PMEA-N1)]3+ complex were determined and in part estimated (UV spectrophotometry and potentiometric pH titration): The release of the proton from the (N7)H+ site in H4[(Dien)Pt(PMEA-N1)]3+ occurs with a rather low pKa (= 0.52+/-0.10). The release of the proton from the -P(O)2(OH) group (pKa = 6.69+/-0.03) in H[(Dien)Pt(PMEA-N1)]+ is only slightly affected by the N1-coordinated (Dien)Pt2+ unit. Comparison with the acidic properties of the H[(Dien)Pt(PMEA-N7)]+ species provides evidence that in the (Dien)Pt(PMEA-N7) complex in aqueous solution an intramolecular, outer-sphere macrochelate is formed through hydrogen bonds between the -PO3(2-) residue of PMEA2- and a PtII-coordinated (Dien)NH2 group; its formation degree amounts to about 40%. The stability constants of the M[(Dien)Pt(PMEA-N1)]2+ complexes with M2+ = Mg2+, Ca2+, Ni2+, Cu2+ and Zn2+ were measured by potentiometric pH titrations in aqueous solution at 25 degrees C and I = 0.1 M (NaNO3). Application of previously determined straight-line plots of log K(M(R-PO3))M versus pK(H(R-PO3)H for simple phosph(on)ate ligands. R-PO3(2-), where R represents a non-inhibiting residue without an affinity for metal ions, proves that the primary binding site of (Dien)Pt(PMEA-N1) is the phosphonate group with all metal ions studied; in fact, Mg2+, Ca2+ and Ni2+ coordinate (within the error limits) only to this site. For the Cu[(Dien)Pt(PMEA-N1)]2+ and Zn[(Dien)Pt(PMEA-N1)]2- systems also the formation of five-membered chelates involving the ether oxygen of the -CH2-O-CH2-PO3(2-) residue could be detected; the formation degrees are about 60% and 30%, respectively. The metal-ion-binding properties of the isomeric (Dien)Pt(PMEA-N7) species studied previously differ in so far that the resulting M[(Dien)Pt(PMEA-N7)]2+ complexes are somewhat less stable, but again Cu2+ and Zn2+ also form with this ligand comparable amounts of the mentioned five-membered chelates. In contrast, both M[(Dien)Pt(PMEA-N1/N7)]2+ complexes differ from the parent M(PMEA) complexes considerably; in the latter instance the formation of the five-membered chelates is of significance for all divalent metal ions studied. The observation that divalent metal-ion binding to the phosphonate group of (Dien)Pt(PMEA-N1) and (Dien)Pt(PMEA-N7) is only moderately inhibited (about 0.2-0.4 log units) by the twofold positively charged (Dien)Pt2+ unit at the adenine residue allows the general conclusion, considering that PMEA is a nucleotide analogue, that this is also true for nucleotides and that consequently participation of, for example, two metal ions in an enzymatic process involving nucleotides is not seriously hampered by charge repulsion.

Adenine↗
PubMed2001

Metal-modified nucleobase sextet: joining four linear metal fragments (trans-a2PtII) and six model nucleobases to an exceedingly stable entity.

Crosslinking of three different model nucleobases (9-ethyladenine, 9-EtA; 9-ethylguanine, 9-EtGH; 1-methyluracil, 1-MeU) by two linear trans-aPtII (a = NH3 or CH3NH2) entities leads to a flat metal-modified base triplet, trans,trans-[(NH3)2Pt(1-MeU-N3)(mu-9-EtA-N7,N1)Pt(CH3NH2)2(9-EtGH-N7)]3+ (4b). Upon hemideprotonation of the 9-ethylguanine base at the N1 position. 4b spontaneously dimerizes to the metalated nucleobase sextet 5, [(4b)(triple bond)(4b-H)]5+. In this dimeric structure a neutral and an anionic guanine ligand, which are complementary to each other, are joined through three H bonds and additionally by two H bonds between guanine and uracil nucleobases. Four additional interbase H bonds maintain the approximate coplanarity of all six bases. The two base triplets form an exceedingly stable entity (KD = 500 +/- 150 M(-1) in DMSO), which is unprecedented in nucleobase chemistry. The precursor of 4b and several related complexes are described and their structures and solution properties are reported.

Base Pairing↗
PubMed2001

Thymine-metal ion interactions: relevance for thymine quartet structures.

Apart from their function as counter ions for the charge neutralization of nucleic acids, alkali metal ions play important roles in stabilizing particular multistranded nucleic acids, e.g. guanine quartets in telomeres and uracil (U) or thymine (T) quartets. Here X-ray crystal structure determinations of a series of alkali metal ions (Na+, K+, Rb+, Cs+) as well as of Mg2+ and H5O2+ adducts with the model bases 1-methylthymine and 1-ethylthymine are reported, which bear relevance to the question of thymine quartet (T4) geometries. The compounds isolated differ in their stoichiometries (T:M = 4:1, 2:1, 1:1), and the ways the metal ions interact with the bases. The two extremes are exclusive metal coordination to exocyclic oxygen atoms of the T bases and exclusive H bonding between M aqua cations and the bases.

Binding Sites↗
PubMed2000

Self-assembly of palladium(II) and platinum(II) complexes of 2-hydroxypyrimidine to novel metallacalix[4]arenes. Receptor properties through multiple H-bonding interactions.

Reaction of [enM(H2O)2](NO3)2 (en = ethylenediamine, M = PdII, PtII) with 2-hydroxypyrimidine (Hpymo) in water results in self-assembly to cyclic complexes of type [enM(pymo-N1,N3)]4(NO3)4 (1, M = PdII; 2, M = PtII) which are structurally analogous to calix[4]arenes. The tetranuclear cations in compounds 1 and 2 adopt, in the solid state, a 1,3-alternate orientation of the pymo residues. Attempts to coordinate either soft (PdII, PtII), borderline (CuII, ZnII), or hard (LaIII, BeII, NaI) metal ions to the oxo surface of the metallacalix[4]arene lower rim were fruitless. In fact, X-ray studies performed on [[enPt(pymo-N1,N3)]4(ClO4)4]2.[Cu(H2O)6](ClO4)2.9H2O (4) showed that multiple H-bonding interactions between the water coordination sphere of the copper center and the oxo surface of two tetranuclear cations take place instead of a direct interaction between the heterometal and the oxo surface of the metallacalix[4]arene. Encapsulation of [Cu(H2O)6]2+ is also responsible for the stabilization of the pinched-cone conformation of the tetranuclear cations in 4. pH* dependent 1H NMR spectra of compounds 1 and 2 indicate a very low basicity of the O-donor group of the pymo residues, revealing no protonation of this position down to pH* 0. Moreover, recrystallization of 2 from strongly acidic aqueous solution (approximately 1 M HClO4) affords the adduct [[enPt(pymo-N1,N3)]4(ClO4)4]2.[H20O8](ClO4)4 (6). Analogously to 4, the cationic [H20O8]4+ species is sandwiched between two tetranuclear cations as a result of multiple H-bonding interactions with the oxo surface of two metallacalix[4]arenes. Again a pinched-cone orientation of the pymo residues is realized.

Journal Article↗
PubMed2000

From simple trans-[a2Pt(2-hydroxypyrimidine)2]2+ (a = NH3, CH3NH2) complexes to structures of higher complexity. Molecular recognition of 2-aminopyrimidine by hydrogen bond formation and reactivity toward additional metal ions.

The new complexes trans-[a2Pt(Hpymo-N1)2]X2 (a = NH3, X = NO3 (1a); a = CH3NH2, X = NO3 (1b); a = CH3NH2, X = ClO4 (1c); Hpymo = 2-hydroxypyrimidine) have been prepared by reaction of trans-[a2Pt(H2O)2]-X2 with 2-hydroxypyrimidine at 80 degrees C in water. Complex 1c cocrystallizes in water with 2-aminopyrimidine (ampym) through formation of complementary pairs of hydrogen bonds to give the supramolecular hexagon [trans-[(CH3NH2)2Pt(pymo-N1)(Hpymo-N1)].Hampym[2(ClO4)4 (2). Molecular recognition of ampym by 1c is responsible for a conformational change of the two hydroxypyrimidine ligands in 1c from anti (1c) to syn and in addition for a proton transfer from a Hpymo residue to ampym against 1.5 units of pKa gradient. 1H NMR concentration-dependent studies as well as NOE experiments in dmso-d6 and dmf-d7 show that 2 dissociates in solution. Compound 1a reacts in NH3:H2O (1:3) with AgI to give the polymeric species [trans-[(NH3)2Pt(mu-pymo-N1,N3)2Ag(H2O)]-NO3]n (3). In contrast to 2, in the polymeric structure the trans-[NH3)2Pt(pymo)2] entities adopt an anti conformation. Nevertheless, the [(H2O)Ag(pymo)2] residues present a syn conformation that leads to a meander-like global structure. Compounds 1b, 1c, 2, and 3 have been studied by X-ray crystallography: (1b) triclinic space group, P1, a = 9.300(2) A, b = 10.483(2) A, c = 11.050(2) A, alpha = 68.21(3) degrees, beta = 75.47(3) degrees, gamma = 73.83(3) degrees, Z = 2, R1 = 0.025, and wR2 = 0.062; (1c) triclinic space group, P1, a = 5.692(1) A, b = 7.758(2) A, c = 11.236(2) A, alpha = 93.12(3) degrees, beta = 92.86(3) degrees, gamma = 102.58(3) degrees, Z = 2, R1 = 0.048, and wR2 = 0.119; (2) triclinic space group, P1, a = 8.355(2) A, b = 11.221(2) A, c = 13.004(3) A, alpha = 86.76(3) degrees, beta = 78.62(3) degrees, gamma = 77.96(3) degrees, Z = 2, R1 = 0.033, and wR2 = 0.080; (3) monoclinic space group, C2/c, a = 5.345(1) A, b = 23.998(5) A, c = 12.474(2) A, beta = 102.27(3) degrees, Z = 8, R1 = 0.041, and wR2 = 0.093.

Journal Article↗
PubMed2000

Isomeric equilibria in aqueous solution involving aromatic ring stacking in the sexternary complexes formed by the quaternary cis-(NH3)2Pt(2'-deoxyguanosine-N7)(dGMP-N7) complex and the binary Cu(2,2'-bipyridine)2+ or Cu(1,10-phenanthroline)2+ complexes (dGMP2- = 2'-deoxyguanosine 5'-monophosphate).

To the best of our knowledge, for the first time the stabilities of sexternary complexes are determined by potentiometric pH titrations in aqueous solution at 25 degrees C and I = 0.1 M (NaNO3). The sexternary complexes form by binding of the binary Cu(Arm)2+ complexes, where Arm = 2,2'-bipyridine (Bpy) or 1,10-phenanthroline (Phen), to the -PO3(2-) group present in the quaternary cis-(NH3)2Pt(dGuo)(dGMP) complex. It is shown by stability constant comparisons and spectrophotometric measurements (observation of charge-transfer bands for the Phen system) that the [cis-(NH3)2Pt(dGuo)(dGMP).Cu(Arm)]2+ complexes can fold in such a way that aromatic ring stacking between the aromatic rings of Bpy or Phen and a guanine residue (most probably the one of dGMP2-) becomes possible. The formation degree of the stacks reaches approximately 25 and 50% for the [cis-(NH3)2Pt-(dGuo)(dGMP).Cu(Bpy)]2+ and [cis-(NH3)2Pt(dGuo)(dGMP).Cu(Phen)]2+ species, respectively. By comparisons with Cu(Arm)(dGMP) complexes, it is shown that the cis-(NH3)2Pt2+ unit coordinated to N7 of the guanine residues in the sexternary complexes inhibits stacking but does not prevent it. This result is of general importance because it demonstrates that in aqueous solution purine residues of nucleotides or nucleic acids that carry a metal ion at N7 can still undergo stacking interactions with other suitable aromatic ring systems.

Algorithms↗
PubMed2000

Solid-Phase Synthesis of a Monofunctional trans-a(2)Pt(II) Complex Tethered to a Single-Stranded Oligonucleotide.

Cross-linking ability is possible with the oligonucleotide-tethered, monofunctional trans-Pt(II) complex shown. It was synthesized by a novel solid-phase approach comprising conjugation of immobilized tetrathymidylic acid with a trans-a(2)Pt(II) building unit, ammonolysis, and transformation of the resulting complex (R=1-N-cyclohexylmethylthyminate) into the chloro derivative (R=Cl). a=NH(2)CH(3), T=thymine.

Journal Article↗
PubMed2000

Effects of N7-methylation, N7-platination, and C8-hydroxylation of guanine on H-bond formation with cytosine: platinum coordination strengthens the Watson-Crick pair.

The hydrogen bonding properties of 1-methylcytosine (1-MeC) with the following guanine base derivatives have been studied in DMSO-d6, applying concentration-dependent 1H NMR spectroscopy: 9-ethylguanine, 7,9-dimethylguanine (7,9-DimeGH+), and 7,8-dihydro-8-oxo-9-methylguanine (8-O-9-MeGH), as well as three 9-ethylguanine complexes carrying different Pt(II) moieties at the N7 position. The association constants K for the Watson-Crick pairing schemes are by a factor 2-3 higher in the cases of platinated guanine complexes compared to the Watson-Crick pair between 9-ethylguanine and 1-methylcytosine (K = 6.9 +/- 1.3 M(-1)). Similar enhanced stabilities are observed for the pairs formed between 1-MeC and 7,9-DimeGH+ or 8-O-9-MeGH. The increase in N1H acidity of the guanine derivative upon modification at the N7 or C8 positions can be correlated with the association constants K; the result is a bell-shaped curve meaning that acidification initially stabilizes hydrogen bond formation up to a certain maximum; further acidification then leads to a destabilization. For two of the examples studied in solution, hydrogen bonding according to Watson-Crick between N7-platinated 9-ethylguanine and 1-methylcytosine has also been established by X-ray crystallography.

Crystallography, X-Ray↗
PubMed2000

Parallel-stranded DNA with Hoogsteen base pairing stabilized by a trans-[Pt(NH3)2]2+ cross-link: characterization and conversion into a homodimer and a triplex.

The oligonucleotides 5'-d(TTTTCTTTTG) and 5'-d(AAAAGAAAAG) were cross-linked with a trans-[Pt(NH3)2]2+ entity via the N7 positions of the 3'-end guanine bases to give parallel-stranded (ps) DNA. At pH 4.2, CD and NMR spectroscopy indicate the presence of Hoogsteen base pairing. In addition, temperature-dependent UV spectroscopy shows an increase in melting temperature for the platinated duplex (35 degrees C) as compared to the non-platinated, antiparallel-stranded duplex formed from the same oligonucleotides (21 degrees C). A monomer-dimer equilibrium for the platinated 20mer is revealed by gel electrophoresis. At pH 4.2, addition of a third strand of composition 5'-d(AGCTTTTCTTTTAG) to the ps duplex leads to the formation of a triple helix with two distinct melting points at 38 degrees C (platinum cross-linked Hoogsteen part) and 21 degrees C (Watson-Crick part), respectively.

Base Pairing↗
PubMed2000

Heavy metal mutagenicity: insights from bioinorganic model chemistry.

The mutagenicity of metal species may be the result of a direct interaction with the target molecule DNA. Possible scenarios leading to nucleobase mispairing are discussed, and selected examples are presented. They include changes in nucleobase selectivity as a consequence of alterations in acid-base properties of nucleobase atoms and groups involved in complementary H bond formation, guanine deprotonation, and stabilization of rare nucleobase tautomers by metal ions. Oxidative nucleobase damage brought about by metal species will not be considered.

Base Pairing↗
PubMed1999

Reactivity of an extremely sterically crowded monofunctional Pt complex, [Pt(1-MeC-N3)3(H2O)]2+ (1-MeC = 1-methylcytosine), toward model nucleobases and selectivity toward guanine in single- and double-stranded deoxyoligonucleotides.

Reactions of [Pt(1-MeC-N3)3Cl]NO3 (1-MeC-N3 = 1-methylcytosine, bound to Pt via N3) and the respective aqua species [Pt(1-MeC-N3)3(H2O)]2+ with the model nucleobases 9-ethylguanine (9-EtGH), 9-methyladenine (9-MeA), single-stranded 5'd(T3GT3), and double-stranded [5'd(GA-GA2GCT2CTC)]2 have been studied in solution by means of 1H NMR spectroscopy, HPLC, and electrospray ionization mass spectrometry. Reactions are generally slow, in particular with the chloro species, and guanine is the only reactive base in the oligonucleotides. However, unlike (dien)PtII, which binds randomly to the guanines in the ds dodecamer, (1-MeC-N3)3PtII binds selectively to the terminal guanine only, probably because base fraying takes place at the duplex ends. The X-ray crystal structures of [Pt(1-MeC-N3)3(9-EtG-N7)]ClO4.8H2O (1b) and of [Pt(1-MeC-N3)3(9-MeA-N7)](ClO4)2.0.5H2O as well as NMR spectroscopic studies of [Pt(1-MeC-N3)3(9-EtGH-N7)] (NO3)2.H2O (1a) are reported. The tetrakis(nucleobase) complexes adopt a head-tail-head orientation of the three 1-MeC bases and an orientation of the fourth base (purine) that permits a maximum of intracomplex H bonds between exocyclic groups. As far as the guanine adduct (1a, 1b) is concerned, relative orientations of the four bases are identical in the model and in the oligonucleotide adduct.

DNA↗
PubMed1999

Metal ions in non-complementary DNA base pairs: an ab initio study of Cu(I), Ag(I), and Au(I) complexes with the cytosine-adenine base pair.

Ab initio calculations have been carried out to characterize the structure and energetics of a silver(I) complex with the cytosine-adenine DNA base pair and an aqua ligand in the coordination sphere of Ag. In addition, we have also studied analogous complexes with Cu(I) and Au(I), and structures in which adenine has been replaced by purine in order to investigate the structural role of the adenine amino group. The calculations revealed that all metal-modified structures are dominated by the metal-base interactions, while the water-metal ion interaction and many-body interligand repulsion are less important contributions. Nevertheless, the structural role of the water molecule in the complex is quite apparent and in agreement with an earlier crystallographic study. The metal-modified base pairs exhibit large conformational flexibility toward out-of-plane motions (propeller twist and buckle), comparable or, in some cases, even larger than that observed in the base pairs without metal ions. All structures have been optimized within the Hartree-Fock approximation, while interaction energies were evaluated with the inclusion of electron correlation.

Adenine↗
PubMed1999

trans-(NH3)(2)Pt(II)-modified deoxyoligonucleotides as potential antisense agents: cross-linking reactions between two 12-mers.

An approach is presented which probes the possible use of trans-[(NH3)(2)PtCl](+)-modified deoxyoligonucleotides in the antisense strategy. It consists of (1) the selective platination of an oligonucleotide containing 11 pyrimidine (T, C) bases as well as a single guanine (G) as a Pt-anchoring group at the 5'-end to give trans-[(NH3)(2)Pt¿5'-d(G(N7)T(2)C(2)T(2)C(2)T(2)C¿Cl](10-) 1 ("antisense strand") and (2) subsequent hybridization with the purine 12-mer 5'-d(GA(2)G(2)A(2)G(2)A(2)G)(11-) ("sense strand"). According to HPLC, three major species 2-4 are formed during reaction (2), all of which are cross-linking adducts between 1 and the sense strand, as confirmed by ESI MS and melting temperature measurements. Only for the major product 3 can a structure be proposed on the basis of 1D and 2D NMR spectra. According to these, G(1) of the antisense strand is cross-linked with G(20) via trans-(NH3)(2)Pt(II). The complementary overhangs of the duplex represent "sticky ends" and are, in principle, capable of associating into multimers of the duplex.

Cisplatin↗
PubMed1999

5,5'-Diuracilyl Species from Uracil and

Not only UV radiation can bring about the dimerization of the pyrimidine nucleobase uracil, a metal ion can as well! The reaction proceeds by a reductive elimination process of two cis-oriented uracil entities, each bonded to Au(III) through C5 [Eq. (a)]. R/R'=H/CH(3), CH(3)/CH(3), H,C(5)H(9)O(4)

Journal Article↗